tbuckley/cabot-search huggingface dataset:
TREM2 splice isoforms generate soluble TREM2 species that disrupt long-term potentiation
Authors: Miguel Moutinho, Israel Coronel, Andy P. Tsai, Gonzalo Viana Di Prisco, Taylor Pennington, Brady K. Atwood, Shweta S. Puntambekar, Daniel C. Smith, Pablo Martinez, Seonggyun Han, Younghee Lee, Cristian A. Lasagna-Reeves, Bruce T. Lamb, Stephanie J. Bissel, Kwangsik Nho, Gary E. Landreth
Journal: Genome Medicine (2023)

Abstract Background TREM2 is a transmembrane receptor expressed by myeloid cells and acts to regulate their immune response. TREM2 governs the response of microglia to amyloid and tau pathologies in the Alzheimer’s disease (AD) brain. TREM2 is also present in a soluble form (sTREM2), and its CSF levels fluctuate as a function of AD progression. Analysis of stroke and AD mouse models revealed that sTREM2 proteins bind to neurons, which suggests sTREM2 may act in a non-cell autonomous manner to influence neuronal function. sTREM2 arises from the proteolytic cleavage of the membrane-associated receptor. However, alternatively spliced TREM2 species lacking a transmembrane domain have been postulated to contribute to the pool of sTREM2. Thus, both the source of sTREM2 species and its actions in the brain remain unclear. Methods The expression of TREM2 isoforms in the AD brain was assessed through the analysis of the Accelerating Medicines Partnership for Alzheimer’s Disease Consortium transcriptomics data, as well as qPCR analysis using post-mortem samples of AD patients and of the AD mouse model 5xFAD. TREM2 cleavage and secretion were studied in vitro using HEK-293T and HMC3 cell lines. Synaptic plasticity, as evaluated by induction of LTP in hippocampal brain slices, was employed as a measure of sTREM2 actions. Results Three distinct TREM2 transcripts, namely ENST00000373113 (TREM2 230 ), which encodes the full-length transmembrane receptor, and the alternatively spliced isoforms ENST00000373122 (TREM2 222 ) and ENST00000338469 (TREM2 219 ), are moderately increased in specific brain regions of patients with AD. We provide experimental evidence that TREM2 alternatively spliced isoforms are translated and secreted as sTREM2. Furthermore, our functional analysis reveals that all sTREM2 species inhibit LTP induction, and this effect is abolished by the GABAA receptor antagonist picrotoxin. Conclusions TREM2 transcripts can give rise to a heterogeneous pool of sTREM2 which acts to inhibit LTP. These results provide novel insight into the generation, regulation, and function of sTREM2 which fits into the complex biology of TREM2 and its role in human health and disease. Given that sTREM2 levels are linked to AD pathogenesis and progression, our finding that sTREM2 species interfere with LTP furthers our understanding about the role of TREM2 in AD.
Nivolumab with or without ipilimumab in pediatric patients with high-grade CNS malignancies: Safety, efficacy, biomarker, and pharmacokinetics—CheckMate 908
Authors: Ira J Dunkel, François Doz, Nicholas K Foreman, Darren Hargrave, Alvaro Lassaletta, Nicolas André, Jordan R Hansford, Tim Hassall, Matthias Eyrich, Sridharan Gururangan, Ute Bartels, Amar Gajjar, Lisa Howell, Deepti Warad, Misena Pacius, Rachel Tam, Yu Wang, Li Zhu, Kenneth Cohen
Journal: Neuro-Oncology (2023)

Abstract Background Therapeutic options are limited in pediatric CNS malignancies. CheckMate 908 (NCT03130959) is an open-label, sequential-arm, phase 1b/2 study investigating nivolumab (NIVO) and NIVO + ipilimumab (IPI) in pediatric patients with high-grade CNS malignancies. Methods Patients (N = 166) in 5 cohorts received NIVO 3 mg/kg every 2 weeks (Q2W) or NIVO 3 mg/kg + IPI 1 mg/kg every 3 weeks (4 doses) followed by NIVO 3 mg/kg Q2W. Primary endpoints included overall survival (OS; newly diagnosed diffuse intrinsic pontine glioma [DIPG]) and progression-free survival (PFS; other recurrent/progressive or relapsed/resistant CNS cohorts). Secondary endpoints included other efficacy metrics and safety. Exploratory endpoints included pharmacokinetics and biomarker analyses. Results As of January 13, 2021, median OS (80% CI) was 11.7 (10.3–16.5) and 10.8 (9.1–15.8) months with NIVO and NIVO + IPI, respectively, in newly diagnosed DIPG. Median PFS (80% CI) with NIVO and NIVO + IPI was 1.7 (1.4–2.7) and 1.3 (1.2–1.5) months, respectively, in recurrent/progressive high-grade glioma; 1.4 (1.2–1.4) and 2.8 (1.5–4.5) months in relapsed/resistant medulloblastoma; and 1.4 (1.4–2.6) and 4.6 (1.4–5.4) months in relapsed/resistant ependymoma. In patients with other recurrent/progressive CNS tumors, median PFS (95% CI) was 1.2 (1.1–1.3) and 1.6 (1.3–3.5) months, respectively. Grade 3/4 treatment-related adverse-event rates were 14.1% (NIVO) and 27.2% (NIVO + IPI). NIVO and IPI first-dose trough concentrations were lower in youngest and lowest-weight patients. Baseline tumor programmed death ligand 1 expression was not associated with survival. Conclusions NIVO ± IPI did not demonstrate clinical benefit relative to historical data. The overall safety profiles were manageable with no new safety signals.
Publisher Correction: Human early-onset dementia caused by DAP12 deficiency reveals a unique signature of dysregulated microglia
Authors: Yingyue Zhou, Mari Tada, Zhangying Cai, Prabhakar S. Andhey, Amanda Swain, Kelly R. Miller, Susan Gilfillan, Maxim N. Artyomov, Masaki Takao, Akiyoshi Kakita, Marco Colonna
Journal: Nature Immunology (2023)
Genome Size Changes by Duplication, Divergence, and Insertion in<i>Caenorhabditis</i>Worms
Authors: Paula E Adams, Victoria K Eggers, Joshua D Millwood, John M Sutton, Jason Pienaar, Janna L Fierst
Journal: Molecular Biology and Evolution (2023)

Genome size has been measurable since the 1940s but we still do not understand genome size variation. Caenorhabditis nematodes show strong conservation of chromosome number but vary in genome size between closely related species. Androdioecy, where populations are composed of males and self-fertile hermaphrodites, evolved from outcrossing, female-male dioecy, three times in this group. In Caenorhabditis, androdioecious genomes are 10-30% smaller than dioecious species, but in the nematode Pristionchus, androdioecy evolved six times and does not correlate with genome size. Previous hypotheses include genome size evolution through: 1) Deletions and "genome shrinkage" in androdioecious species; 2) Transposable element (TE) expansion and DNA loss through large deletions (the "accordion model"); and 3) Differing TE dynamics in androdioecious and dioecious species. We analyzed nematode genomes and found no evidence for these hypotheses. Instead, nematode genome sizes had strong phylogenetic inertia with increases in a few dioecious species, contradicting the "genome shrinkage" hypothesis. TEs did not explain genome size variation with the exception of the DNA transposon Mutator which was twice as abundant in dioecious genomes. Across short and long evolutionary distances Caenorhabditis genomes evolved through small structural mutations including gene-associated duplications and insertions. Seventy-one protein families had significant, parallel decreases across androdioecious Caenorhabditis including genes involved in the sensory system, regulatory proteins and membrane-associated immune responses. Our results suggest that within a dynamic landscape of frequent small rearrangements in Caenorhabditis, reproductive mode mediates genome evolution by altering the precise fates of individual genes, proteins, and the phenotypes they underlie.
Hepatic mitochondrial NAD+ transporter SLC25A47 activates AMPKα mediating lipid metabolism and tumorigenesis
Authors: Lili Cheng, R.N.V. Krishna Deepak, Guoqiang Wang, Ziyi Meng, Lei Tao, Mengqing Xie, Wenna Chi, Yuming Zhang, Mingming Yang, Yilie Liao, Ruiqun Chen, Yu Liang, Junyu Zhang, Yuedong Huang, Weihua Wang, Zhiying Guo, Yunfang Wang, Jiandie D. Lin, Hao Fan, Ligong Chen
Journal: Hepatology (2023)

Background &amp; Aims: SLC25A47 was initially identified as a mitochondrial HCC-downregulated carrier protein, but its physiological functions and transport substrates are unknown. We aimed to investigate the physiological role of SLC25A47 in hepatic metabolism. Approach &amp; Results: In the treatment of hepatocytes with metformin, we found that metformin can transcriptionally activate the expression of Slc25a47 , which is required for AMP-activated protein kinase α (AMPKα) phosphorylation. Slc25a47 -deficient mice had increased hepatic lipid content, triglycerides, and cholesterol levels, and we found that Slc25a47 deficiency suppressed AMPKα phosphorylation and led to an increased accumulation of nuclear SREBPs, with elevated fatty acid and cholesterol biosynthetic activities. Conversely, when Slc25a47 was overexpressed in mouse liver, AMPKα was activated and resulted in the inhibition of lipogenesis. Moreover, using a diethylnitrosamine-induced mouse HCC model, we found that the deletion of Slc25a47 promoted HCC tumorigenesis and development through the activated mammalian target of rapamycin cascade. Employing homology modeling of SLC25A47 and virtual screening of the human metabolome database, we demonstrated that NAD + was an endogenous substrate for SLC25A47, and the activity of NAD + -dependent sirtuin 3 declined in Slc25a47 -deficient mice, followed by inactivation of AMPKα. Conclusions: Our findings reveal that SLC25A47, a hepatocyte-specific mitochondrial NAD + transporter, is one of the pharmacological targets of metformin and regulates lipid homeostasis through AMPKα, and may serve as a potential drug target for treating NAFLD and HCC.
siVAE: interpretable deep generative models for single-cell transcriptomes
Authors: Yongin Choi, Ruoxin Li, Gerald Quon
Journal: Genome biology (2023)

Abstract Neural networks such as variational autoencoders (VAE) perform dimensionality reduction for the visualization and analysis of genomic data, but are limited in their interpretability: it is unknown which data features are represented by each embedding dimension. We present siVAE, a VAE that is interpretable by design, thereby enhancing downstream analysis tasks. Through interpretation, siVAE also identifies gene modules and hubs without explicit gene network inference. We use siVAE to identify gene modules whose connectivity is associated with diverse phenotypes such as iPSC neuronal differentiation efficiency and dementia, showcasing the wide applicability of interpretable generative models for genomic data analysis.
Not1 and Not4 inversely determine mRNA solubility that sets the dynamics of co-translational events
Authors: George Allen, Benjamin Weiss, Olesya O. Panasenko, Susanne Huch, Zoltan Villanyi, Benjamin Albert, Daniel Dilg, Marina Zagatti, Paul Schaughency, Susan E. Liao, Jeff Corden, Christine Polte, David Shore, Zoya Ignatova, Vicent Pelechano, Martine A. Collart
Journal: Genome biology (2023)

The Ccr4-Not complex is mostly known as the major eukaryotic deadenylase. However, several studies have uncovered roles of the complex, in particular of the Not subunits, unrelated to deadenylation and relevant for translation. In particular, the existence of Not condensates that regulate translation elongation dynamics has been reported. Typical studies that evaluate translation efficiency rely on soluble extracts obtained after the disruption of cells and ribosome profiling. Yet cellular mRNAs in condensates can be actively translated and may not be present in such extracts.
Exploring the Relationship Between Efpeglenatide Dose and Cardiovascular Outcomes in Type 2 Diabetes: Insights From the AMPLITUDE-O Trial
Authors: Hertzel C. Gerstein, Zhuoru Li, Chinthanie Ramasundarahettige, Seungjae Baek, Kelley R.H. Branch, Stefano Del Prato, Carolyn S.P. Lam, Renato D. Lopes, Richard Pratley, Julio Rosenstock, Naveed Sattar
Journal: Circulation (2023)

Background: In the AMPLITUDE-O (Effect of Efpeglenatide on Cardiovascular Outcomes) cardiovascular outcomes trial, adding either 4 mg or 6 mg weekly of the glucagon-like peptide-1 receptor agonist efpeglenatide to usual care reduced major adverse cardiovascular events (MACE) in people with type 2 diabetes at high cardiovascular risk. Whether these benefits are dose related remains uncertain. Methods: Participants were randomly assigned in a 1:1:1 ratio to placebo, 4 mg or 6 mg of efpeglenatide. The effect of 6 mg versus placebo and of 4 mg versus placebo on MACE (a nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular or unknown causes) and on all the secondary composite cardiovascular and kidney outcomes was assessed. A dose-response relationship was assessed using the log-rank test and χ 2 statistic for trend. Results: During a median follow-up of 1.8 years, MACE occurred in 125 (9.2%) participants assigned to placebo, 84 (6.2%) participants assigned to 6 mg of efpeglenatide (hazard ratio [HR], 0.65 [95% CI, 0.5–0.86]; P =0.0027), and 105 (7.7%) assigned to 4 mg of efpeglenatide (HR, 0.82 [95% CI, 0.63–1.06]; P =0.14). Participants receiving high-dose efpeglenatide also experienced fewer secondary outcomes, including the composite of MACE, coronary revascularization, or hospitalization for unstable angina (HR, 0.73 for 6 mg, P =0.011; HR, 0.85 for 4 mg, P =0.17), a kidney composite outcome comprising sustained new macroalbuminuria, a ≥40% decline in estimated glomerular filtration rate or renal failure (HR, 0.63 for 6 mg, P &lt;0.0001; HR, 0.73 for 4 mg, P =0.0009), MACE or any death (HR, 0.67 for 6 mg, P =0.0021; HR, 0.81 for 4 mg, P =0.08), a kidney function outcome comprising a sustained ≥40% decline in estimated glomerular filtration rate, renal failure, or death (HR, 0.61 for 6 mg, P =0.0072; HR, 0.97 for 4 mg, P =0.83), and the composite of MACE, any death, heart failure hospitalization, or the kidney function outcome (HR, 0.63 for 6 mg, P =0.0002; HR, 0.81 for 4 mg, P =0.067). A clear dose-response was noted for all primary and secondary outcomes (all P for trend ≤0.018). Conclusions: The graded salutary relationship between efpeglenatide dose and cardiovascular outcomes suggests that titrating efpeglenatide and potentially other glucagon-like peptide-1 receptor agonists to high doses may maximize their cardiovascular and renal benefits. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03496298.
Impact of sex on outcomes in patients with hairy cell leukemia. An <scp>HCL</scp> patient data registry analysis
Authors: Narendranath Epperla, Qiuhong Zhao, Mirela Anghelina, Jasmine Neal, James S. Blachly, Kerry A. Rogers, Gerard Lozanski, Christopher C. Oakes, Seema A. Bhat, Clive S. Zent, Versha Banerji, Michael Grever, Leslie A. Andritsos
Journal: American Journal of Hematology (2023)
Eliminating the monitoring period with subcutaneous daratumumab: a single-center experience
Authors: Kathryn T. Maples, Kevin H. Hall, Nisha S. Joseph, Craig C. Hofmeister, Vikas Gupta, Madhav V. Dhodapkar, Jonathan L. Kaufman, Ajay K. Nooka, Sagar Lonial
Journal: Blood Cancer Journal (2023)
<i>Vibrio parahaemolyticus</i> T6SS2 effector repertoires
Authors: Daniel Tchelet, Kinga Keppel, Eran Bosis, Dor Salomon
Journal: Gut Microbes (2023)

All strains of the marine bacterium Vibrio parahaemolyticus harbor a type VI secretion system (T6SS) named T6SS2, suggesting that this system plays an important role in the life cycle of this emerging pathogen. Although T6SS2 was recently shown to play a role in interbacterial competition, its effector repertoire remains unknown. Here, we employed proteomics to investigate the T6SS2 secretome of two V. parahaemolyticus strains, and we identified several antibacterial effectors encoded outside of the main T6SS2 gene cluster. We revealed two T6SS2-secreted proteins that are conserved in this species, indicating that they belong to the core secretome of T6SS2; other identified effectors are found only in subsets of strains, suggesting that they comprise an accessory effector arsenal of T6SS2. Remarkably, a conserved Rhs repeat-containing effector serves as a quality control checkpoint and is required for T6SS2 activity. Our results reveal effector repertoires of a conserved T6SS, including effectors that have no known activity and that have not been previously associated with T6SSs.
Gut microbiome composition is associated with long-term disability worsening in multiple sclerosis
Authors: Lindsay Devolder, Ayla Pauwels, Ann Van Remoortel, Gwen Falony, Sara Vieira-Silva, Guy Nagels, Jacques De Keyser, Jeroen Raes, Marie B. D’Hooghe
Journal: Gut Microbes (2023)

Predicting the long-term outcome of multiple sclerosis (MS) remains an important challenge to this day. As the gut microbiota is emerging as a potential player in MS, we investigated in this study whether gut microbial composition at baseline is related to long-term disability worsening in a longitudinal cohort of 111 MS patients. Fecal samples and extensive host metadata were collected at baseline and 3 months post-baseline, with additional repeated neurological measurements performed over (median) 4.4 y. Worsening (with EDSS-Plus) occurred in 39/95 patients (outcome undetermined for 16 individuals). The inflammation-associated, dysbiotic Bacteroides 2 enterotype (Bact2) was detected at baseline in 43.6% of worsened patients, while only 16.1% of non-worsened patients harbored Bact2. This association was independent of identified confounders, and Bact2 was more strongly associated with EDSS-Plus than neurofilament light chain (NfL) plasma levels. Furthermore, using fecal sampling performed 3 months post-baseline, we observed Bact2 to be relatively stable, suggesting its potential use as a prognostic biomarker in MS clinical practice.
Randomized controlled trial demonstrates response to a probiotic intervention for metabolic syndrome that may correspond to diet
Authors: Hannah C. Wastyk, Dalia Perelman, Madeline Topf, Gabriela K. Fragiadakis, Jennifer L. Robinson, Justin L. Sonnenburg, Christopher D. Gardner, Erica D. Sonnenburg
Journal: Gut Microbes (2023)

An individual's immune and metabolic status is coupled to their microbiome. Probiotics offer a promising, safe route to influence host health, possibly via the microbiome. Here, we report an 18-week, randomized prospective study that explores the effects of a probiotic vs. placebo supplement on 39 adults with elevated parameters of metabolic syndrome. We performed longitudinal sampling of stool and blood to profile the human microbiome and immune system. While we did not see changes in metabolic syndrome markers in response to the probiotic across the entire cohort, there were significant improvements in triglycerides and diastolic blood pressure in a subset of probiotic arm participants. Conversely, the non-responders had increased blood glucose and insulin levels over time. The responders had a distinct microbiome profile at the end of the intervention relative to the non-responders and placebo arm. Importantly, diet was a key differentiating factor between responders and non-responders. Our results show participant-specific effects of a probiotic supplement on improving parameters of metabolic syndrome and suggest that dietary factors may enhance stability and efficacy of the supplement.
Mitochondrial TXNRD2 and ME3 Genetic Risk Scores Are Associated with Specific Primary Open-Angle Glaucoma Phenotypes
Authors: Inas F. Aboobakar, Tyler G. Kinzy, Yan Zhao, Baojian Fan, Louis R. Pasquale, Ayub Qassim, Antonia Kolovos, Joshua M. Schmidt, Jamie E. Craig, Jessica N. Cooke Bailey, Janey L. Wiggs, R. Rand Allingham, Murray Brilliant, Donald L. Budenz, Jessica N. Cooke Bailey, John H. Fingert, Douglas Gaasterland, Teresa Gaasterland, Jonathan L. Haines, Michael A. Hauser, Richard K. Lee, Paul R. Lichter, Yutao Liu, Syoko Moroi, Jonathan Myers, Louis R. Pasquale, Margaret Pericak-Vance, Anthony Realini, Doug Rhee, Julia E. Richards, Robert Ritch, Joel S. Schuman, William K. Scott, Kuldev Singh, Arthur J. Sit, Douglas Vollrath, Robert N. Weinreb, Janey L. Wiggs, Gadi Wollstein, Donald J. Zack
Journal: Ophthalmology (2023)
Exploiting the biogenesis of extracellular vesicles for bioengineering and therapeutic cargo loading
Authors: Julia Rädler, Dhanu Gupta, Antje Zickler, Samir EL Andaloussi
Journal: Molecular Therapy (2023)

Extracellular vesicles (EVs) are gaining increasing attention for diagnostic and therapeutic applications in various diseases. These natural nanoparticles benefit from favorable safety profiles and unique biodistribution capabilities, rendering them attractive drug-delivery modalities over synthetic analogs. However, the widespread use of EVs is limited by technological shortcomings and biological knowledge gaps that fail to unravel their heterogeneity. An in-depth understanding of their biogenesis is crucial to unlocking their full therapeutic potential. Here, we explore how knowledge about EV biogenesis can be exploited for EV bioengineering to load therapeutic protein or nucleic acid cargos into or onto EVs. We summarize more than 75 articles and discuss their findings on the formation and composition of exosomes and microvesicles, revealing multiple pathways that may be stimulation and/or cargo dependent. Our analysis further identifies key regulators of natural EV cargo loading and we discuss how this knowledge is integrated to develop engineered EV biotherapeutics.
Prevalence and Clinical Implications of Tricuspid Valve Prolapse Based on Magnetic Resonance Diagnostic Criteria
Authors: Andrada C. Guta, Kinan C. El-Tallawi, Duc T. Nguyen, Fatima Qamar, Thuy Nguyen, William A. Zoghbi, Gerald Lawrie, Edward A. Graviss, Dipan J. Shah
Journal: Journal of the American College of Cardiology (2023)